uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (10 of 107) Show all publications
Lau, A., So, R. W. L., Lau, H. H. C., Sang, J. C., Ruiz-Riquelme, A., Fleck, S. C., . . . Watts, J. C. (2020). alpha-Synuclein strains target distinct brain regions and cell types. Nature Neuroscience, 23, 21-31
Open this publication in new window or tab >>alpha-Synuclein strains target distinct brain regions and cell types
Show others...
2020 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 23, p. 21-31Article in journal (Refereed) Published
Abstract [en]

The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of alpha-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived alpha-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral alpha-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-406215 (URN)10.1038/s41593-019-0541-x (DOI)000507601600004 ()31792467 (PubMedID)
Funder
EU, European Research Council, 669237
Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06Bibliographically approved
Danielsson, M., Halvardson, J., Davies, H., Moghadam, B. T., Mattisson, J., Rychlicka-Buniowska, E., . . . Forsberg, L. A. (2020). Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals. European Journal of Human Genetics, 28(3), 349-357
Open this publication in new window or tab >>Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals
Show others...
2020 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 28, no 3, p. 349-357Article in journal (Refereed) Published
Abstract [en]

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397754 (URN)10.1038/s41431-019-0533-z (DOI)000515027800009 ()31654039 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, European Research CouncilStiftelsen Olle Engkvist Byggmästare
Note

These authors contributed equally: Jan P. Dumanski, Lars A. Forsberg

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-04-02Bibliographically approved
Aoyagi, A., Condello, C., Stöhr, J., Yue, W., Rivera, B. M., Lee, J. C., . . . Prusiner, S. B. (2019). A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain. Science Translational Medicine, 11(490), Article ID eaat8462.
Open this publication in new window or tab >>A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain
Show others...
2019 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 11, no 490, article id eaat8462Article in journal (Refereed) Published
Abstract [en]

The hallmarks of Alzheimer's disease (AD) are the accumulation of A beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of A beta in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological A beta conformers. Individuals over 80 years of age had the lowest amounts of prion-like A beta and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-383844 (URN)10.1126/scitranslmed.aat8462 (DOI)000466449900004 ()31043574 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationStockholm County Council
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-05-24Bibliographically approved
Vaikath, N. N., Hmila, I., Gupta, V., Erskine, D., Ingelsson, M. & El-Agnaf, O. M. A. (2019). Antibodies against alpha-synuclein: tools and therapies. Journal of Neurochemistry, 150(5), 612-625
Open this publication in new window or tab >>Antibodies against alpha-synuclein: tools and therapies
Show others...
2019 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 150, no 5, p. 612-625Article, review/survey (Refereed) Published
Abstract [en]

Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of alpha-synuclein (alpha-syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against alpha-syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated alpha-syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full-length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody-based approaches have been found to be promising as therapeutic strategies, both to block alpha-syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different alpha-syn specific antibodies and provide their usefulness in tackling synucleinopathies. 

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
antibodies, synucleinopathies, alpha-synuclein
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-394144 (URN)10.1111/jnc.14713 (DOI)000482407100012 ()31055836 (PubMedID)
Available from: 2019-10-04 Created: 2019-10-04 Last updated: 2019-10-04Bibliographically approved
Reyes, J. F., Sackmann, C., Hoffmann, A., Svenningsson, P., Winkler, J., Ingelsson, M. & Hallbeck, M. (2019). Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes. Acta Neuropathologica, 138(1), 23-47
Open this publication in new window or tab >>Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
Show others...
2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed) Published
Abstract [en]

The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Parkinson's disease (PD), Multiple system atrophy (MSA), Alzheimer's disease (AD), Cell-to-cell transfer, Prion-like transfer, Gap junction proteins, Cx32, GJB1, alpha-Synuclein (-syn)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-390089 (URN)10.1007/s00401-019-02007-x (DOI)000471708700002 ()30976973 (PubMedID)
Funder
Swedish Research Council, 523-2013-2735German Research Foundation (DFG), GRK2162
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved
Åhman, H. B., Giedraitis, V., Cedervall, Y., Lennhed, B., Berglund, L., McKee, K., . . . Åberg, A. C. (2019). Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer's Disease Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 71, S75-S83
Open this publication in new window or tab >>Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer's Disease Cerebrospinal Fluid Biomarkers
Show others...
2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 71, p. S75-S83Article in journal (Refereed) Published
Abstract [en]

Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-beta 42 (A beta(42)), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range 49-84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with "Naming Animals" (TUGdt NA) and "Months Backwards" (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman's rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, attention, biomarkers, cerebrospinal fluid, dementia, executive function, gait, mild cognitive impairment, subjective cognitive impairment
National Category
Geriatrics
Identifiers
urn:nbn:se:uu:diva-395565 (URN)10.3233/JAD-181265 (DOI)000487075000010 ()31104024 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Kunkle, B. W., Giedraitis, V., Kilander, L., Brundin, R., Lannfelt, L., Ingelsson, M. & Pericak-Vance, M. A. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414-430
Open this publication in new window or tab >>Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Show others...
2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 414-430Article in journal (Refereed) Published
Abstract [en]

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379343 (URN)10.1038/s41588-019-0358-2 (DOI)000459947200011 ()30820047 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-019-0358-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Thompson, D. J., Genovese, G., Halvardson, J., Ulirsch, J. C., Wright, D. J., Terao, C., . . . Perry, J. R. (2019). Genetic predisposition to mosaic Y chromosome loss in blood. Nature, 575, 652-657
Open this publication in new window or tab >>Genetic predisposition to mosaic Y chromosome loss in blood
Show others...
2019 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 575, p. 652-657Article in journal (Refereed) Published
Abstract [en]

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397756 (URN)10.1038/s41586-019-1765-3 (DOI)000500036800057 ()31748747 (PubMedID)
Funder
EU, European Research Council, 679744
Note

Lars Forsberg and John Perry contributed equally to this work

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-01-13Bibliographically approved
Quaranta, A., Karlsson, I., Ndreu, L., Marini, F., Ingelsson, M. & Thorsen, G. (2019). Glycosylation profiling of selected proteins in cerebrospinal fluid from Alzheimer's disease and healthy subjects. Analytical Methods, 11(26), 3331-3340
Open this publication in new window or tab >>Glycosylation profiling of selected proteins in cerebrospinal fluid from Alzheimer's disease and healthy subjects
Show others...
2019 (English)In: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 11, no 26, p. 3331-3340Article in journal (Refereed) Published
Abstract [en]

Alteration of glycosylation has been observed in several diseases, such as cancer and neurodegenerative disorders. The study of changes in glycosylation could lead to a better understanding of mechanisms underlying these diseases and to the identification of new biomarkers. In this work the N-linked glycosylation of five target proteins in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and healthy controls have been analyzed for the first time. The investigated proteins, transferrin (TFN), alpha-1-antitrypsin (AAT), C1-inhibitor, immunoglobulin G (IgG), and alpha-1-acid glycoprotein (AGP), were selected based on the availability of VHH antibody fragments and their potential involvement in neurodegenerative and inflammation diseases. AD patients showed alterations in the glycosylation of low abundance proteins, such as C1-inhibitor and alpha-1-acid glycoprotein. These alterations would not have been detected if the glycosylation profile of the total CSF had been analyzed, due to the masking effect of the dominant profiles of high abundance glycoproteins, such as IgG. Information obtained from single proteins was not sufficient to correctly classify the two sample groups; however, by using an advanced multivariate technique a total non-error rate of 72 +/- 3% was obtained. In fact, the corresponding model was able to correctly classify 71 +/- 4% of the healthy subjects and 74 +/- 7% of the AD patients. Even if the results were not conclusive for AD, this approach could be extremely useful for diseases in which glycosylation changes are reported to be more extensive, such as several types of cancer and autoimmune diseases.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-390784 (URN)10.1039/c9ay00381a (DOI)000474140100007 ()
Funder
Swedish Research Council, 2013-4353
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-08-16Bibliographically approved
Hanlon, K. S., Kleinstiver, B. P., Garcia, S. P., Zaborowski, M. P., Volak, A., Spirig, S. E., . . . György, B. (2019). High levels of AAV vector integration into CRISPR-induced DNA breaks. Nature Communications, 10, Article ID 4439.
Open this publication in new window or tab >>High levels of AAV vector integration into CRISPR-induced DNA breaks
Show others...
2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4439Article in journal (Refereed) Published
Abstract [en]

Adeno-associated virus (AAV) vectors have shown promising results in preclinical models, but the genomic consequences of transduction with AAV vectors encoding CRISPR-Cas nucleases is still being examined. In this study, we observe high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in cultured murine neurons, mouse brain, muscle and cochlea. Genome-wide AAV mapping in mouse brain shows no overall increase of AAV integration except at the CRISPR/Cas9 target site. To allow detailed characterization of integration events we engineer a miniature AAV encoding a 465 bp lambda bacteriophage DNA (AAV-lambda 465), enabling sequencing of the entire integrated vector genome. The integration profile of AAV-465 lambda in cultured cells display both full-length and fragmented AAV genomes at Cas9 on-target sites. Our data indicate that AAV integration should be recognized as a common outcome for applications that utilize AAV for genome editing.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-395832 (URN)10.1038/s41467-019-12449-2 (DOI)000488235000009 ()31570731 (PubMedID)
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5466-8370

Search in DiVA

Show all publications